Many aspects of acute and chronic rejection can be affected by complement because split products of complement influence the localization, activation and effector functions of platelets, granulocytes, monocytes, and lymphocytes. Transplants biopsied during acute rejection episodes associated with antibody and complement deposition demonstrate endothelial injury, neutrophil margination, platelet accumulation, and fibrin deposition in capillaries. The complement cascade is a potent, multifaceted mediator of inflammation. Systemic production of complement occurs in the liver, but macrophages, platelets, T-lymphocytes and endothelial cells can produce complement components in local sites of inflammation. The complement cascade can be activated by antibodies through the classical pathway, while injured cells have the potential to initiate complement via the alternative pathway. Once activated, soluble C3a and C5a increase vascular permeability as well as chemotactically attract and activate granulocytes; membrane bound C3b and iC3b increase the attachment of granulocytes and monocyte/macrophages to target cells; and the C5b-C9 membrane attack complex (MAC) aggregates and activates platelets in addition to damaging target cell membranes. C3b and iC3b also modulate developing and ongoing immune responses through complement receptors types l and 2 (CR1 and CR2) on antigen presenting cells, T and B lymphocytes. Complement inhibitors have been more effective than antibody depletion in delaying hyperacute rejection where complement and antibody play a central role. In C6 deficient rats, not only is hyperacute rejection delayed, but survival of allografts in naive recipients is prolonged. These experimental findings are consistent with immunohistological studies of clinical biopsies from acutely rejecting allografts in which deposition of complement components are observed even when little or no antibody is detected. Our working hypothesis is that complement can contribute to multiple aspects of acute and chronic rejection. Our specific aims are to I) Analyze differences in the rejection reaction in C6 deficient versus normal rats; 2) Analyze differences in rejection of allografts subjected to warm ischemia in C6 deficient versus normal rats; 3) Modify specific complement-triggered effector mechanisms in order to define those mechanisms that contribute to allograft injury; and 4) Analyze differences in complement activation and the rejection reaction in agammaglobulinemic versus normal rats. Because most immunosuppressive protocols have been directed at inhibiting cellular immunity, complement-mediated graft injury may be accentuated in the clinical setting. Recombinant human sCR1 and sCR2 have already been found to delay effectively hyperacute rejection in rats and in preclinical primate trails. If these agents also prove effective in delaying acute rejection, then they could have clinical application in rejection episodes that are associated with complement activation.